FoxO3 controls autophagy in skeletal muscle in vivo
FoxO3 controls autophagy in skeletal muscle in vivo
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DOI：
10.1016/j.cmet.2007.11.001
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发表时间：
2007-12-01
期刊：
影响因子：
29
通讯作者：
Sandri, Marco
中科院分区：
文献类型：
--
作者：
Mammucari, Cristina;Milan, Giulia;Sandri, Marco
自噬允许细胞在饥饿期间通过溶酶体酶大量降解蛋白质和细胞器而存活。然而，负责诱导和调节自噬程序的机制知之甚少。在这里，我们表明，FoxO 3转录因子，这在肌肉萎缩中起着关键作用，是必要的和足够的诱导在体内骨骼肌自噬。Akt/PKB激活阻断FoxO 3激活和自噬，并且这种作用不能被雷帕霉素阻止。FoxO 3控制自噬相关基因的转录，包括LC 3和Bnip 3，Bnip 3似乎介导FoxO 3对自噬的影响。蛋白酶体抑制剂不能阻止这种作用。因此，FoxO 3独立地控制骨骼肌中蛋白质分解的两个主要系统，即泛素-蛋白酶体和自噬/溶酶体途径。这些发现指出FoxO 3和Bnip 3是肌肉萎缩性疾病和其他涉及自噬的退行性和肿瘤性疾病的潜在治疗靶点。
Autophagy allows cell survival during starvation through the bulk degradation of proteins and organelles by lysosomal enzymes. However, the mechanisms responsible for the induction and regulation of the autophagy program are poorly understood. Here we show that the FoxO3 transcription factor, which plays a critical role in muscle atrophy, is necessary and sufficient for the induction of autophagy in skeletal muscle in vivo. Akt/PKB activation blocks FoxO3 activation and autophagy, and this effect is not prevented by rapamycin. FoxO3 controls the transcription of autophagy-related genes, including LC3 and Bnip3, and Bnip3 appears to mediate the effect of FoxO3 on autophagy. This effect is not prevented by proteasome inhibitors. Thus, FoxO3 controls the two major systems of protein breakdown in skeletal muscle, the ubiquitin-proteasomal and autophagic/lysosomal pathways, independently. These findings point to FoxO3 and Bnip3 as potential therapeutic targets in muscle wasting disorders and other degenerative and neoplastic diseases in which autophagy is involved.